Folliculin function is highly cell-specific

Whilst trying to elucidate the role of FLCN, a number of studies have reported opposing results. FLCN has been shown to both activate and inhibit mTOR signalling, AMPK signalling and RhoA signalling and to both potentiate and abrogate cell-cell adhesion. It is thought that this may be due to cell type or context-specific factors (Hudon et al., 2010). A new study from Professor Lisa Henske’s team at Harvard Medical School in Boston, USA, has shown that FLCN depletion leads to highly cell specific defects.

In order to investigate how loss of FLCN leads to cystogenesis in the lung, Khabibullin et al. (2014) used siRNAs to downregulate FLCN expression in human bronchial epithelial (HBE) cells, and small airways epithelial cells (SAECs). A reduction of FLCN expression in HBE cells led to reduced AMPK signalling and MAPK signalling, increased TGF-β signalling and cell-cell adhesion, and had no effect on mTOR signalling. Conversely, reduced FLCN expression in SAECs led to increased mTOR signalling, decreased TGF-B signalling and had no effect on AMPK signalling, MAPK signalling, or cell-cell adhesion.

Autophagy, Cofilin phosphorylation, Cox4 expression, and cell doubling remained unaffected, and FLCN expression was predominantly cytoplasmic in both cell lines. These results contrast with those from other studies which show that FLCN stimulates or inhibits autophagy in a variety of cell types (Bastola et al., 2013, Hasumi et al., 2014, Possik et al., 2014); regulates Cofilin phosphorylation in UOK-257 cells (Lu et al., 2014); upregulates Cox4 expression in BHD-associated kidney tumours (Hasumi et al., 2012); delays cell cycle progression in UOK-257 cells (Laviolette et al., 2013); and is localised to the nucleus in UOK-257 cells (Laviolette et al., 2013).

Khabibullin et al. hypothesised that the increased cell-cell adhesion seen in HBE cells may be the underlying cause of lung cyst development, as it may make lung tissue more inflexible and reduce its ability to withstand mechanical forces caused by breathing.

To investigate this hypothesis, the authors analysed whether mice heterozygous for a FLCN deletion developed cystic airspace enlargement either spontaneously or following mechanically induced pulmonary stress (barotrauma). FLCN+/- mice did show a trend towards increased lung elastance following barotrauma, suggesting that the lungs of these mice did not respond to mechanical pressures in the same way as wildtype mice. This lends further support to previous observations that the loss of FLCN causes alveolar walls to become vulnerable to mechanical stress, which causes lung cysts to form (Goncharova et al., 2014, Kumasaka et al., 2013).

Taken together, these studies suggest that FLCN-deletion is likely to cause BHD symptoms through very different mechanisms. Indeed, biallelic FLCN inactivation is required for renal tumourigenesis (Vocke et al., 2005), while FLCN haploinsufficiency appears to cause the skin and lung symptoms of BHD. Thus, it is possible that separate treatments will have to be developed for each BHD symptom. Furthermore, due to the opposing effects of FLCN loss in different cell types, it is possible that the therapy for one symptom may exacerbate another symptom, meaning that therapies may need to be specifically delivered to each organ rather than taken systemically.


  • Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF (2013). Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PloS one, 8 (7) PMID: 23922894
  • Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, & Krymskaya VP (2014). Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell reports, 7 (2), 412-23 PMID: 24726356
  • Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, Klein ME, Takikita S, Nagashima K, Schmidt LS, & Linehan WM (2012). Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. Journal of the National Cancer Institute, 104 (22), 1750-64 PMID: 23150719
  • Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, & Marston Linehan W (2014). Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Human molecular genetics PMID: 24908670
  • Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, Crosby K, Pomerleau V, Uetani N, & Pause A (2010). Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. Journal of medical genetics, 47 (3), 182-9 PMID: 19843504
  • Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, Laucho Contreras M, Zhang E, Parkhitko A, Yu JJ, Owen CA, Huang H, Baron RM, & Henske EP (2014). Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiological reports, 2 (8) PMID: 25121506
  • Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology, 65 (1), 100-10 PMID: 24393238
  • Laviolette LA, Wilson J, Koller J, Neil C, Hulick P, Rejtar T, Karger B, Teh BT, & Iliopoulos O (2013). Human folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations. PloS one, 8 (7) PMID: 23874397
  • Lu X, Boora U, Seabra L, Rabai EM, Fenton J, Reiman A, Nagy Z, & Maher ER (2014). Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene, 33 (8), 956-65 PMID: 23416984
  • Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, & Pause A (2014). Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS genetics, 10 (4) PMID: 24763318
  • Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, & Linehan WM (2005). High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute, 97 (12), 931-5 PMID: 15956655 – the primary online resource for anyone interested in BHD Syndrome.

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